This is a competitive renewal application (in response to RFA-CA-10-006) "Transdisciplinary Research in Energetics and Cancer (U54)". The overarching theme of the Seattle TREC Center will be to determine mechanisms by which changes in energy balance influences cancer development and progression across the adult lifespan in small-scale and population-level human experimental studies. We propose to elucidate new pathways linking energy balance across the cancer continuum from the general population, to high risk individuals, to cancer survivors, using transdisciplinary methods that we developed in the first 5 years of TREC funding and capitalizing on our strengths in conducting human intervention trials. Project 1 will investigate, in a controlled feeding study, the role of caloric restriction plus a low glycemic load diet vs. low glycemic load diet alone in relation to an integrated set of endpoints: systemic insulin resistance and inflammation, adipose tissue inflammation and gut microbial community. Project 2 will test the effect of our group-based modification of the Diabetes Prevention Program weight loss intervention vs. control on prognosis-related biomarkers in breast cancer survivors including systemic metabolic and inflammatory markers, and breast aspirate cytology, proliferation, and gene expression. Project 3 will conduct a randomized trial evaluating a multi-level obesity prevention intervention in small worksites, where the intervention will include work, home, and neighborhood components. Additional novel work in the 3 projects will examine: weight loss effects on proteomics, caloric restriction effects on adipose expression of aromatase, the intersection of gut health with systemic insulin resistance and inflammation, and biology behavior interactions in weight loss and maintenance. Five Cores will support all Projects: the required Administration, Training/Education &Outreach, and Developmental, the recommended Biostatistics/Bioinformatics, and a Laboratory Core. A team of transdisciplinary researchers will collaborate across projects, including experts in epidemiology, oncology, nutrition, biochemistry, endocrinology, biostatistics, and behavioral science. The education/training and outreach program will include individual trainee mentoring and project experience, journal club, seminars, and national and international symposia and meetings on TREC-related topics. We propose to continue our outstanding record of cross-TREC center collaborations, where we have led several multi-center developmental studies. We propose to continue the strong leadership we have brought to the TREC community, and to continue our international leadership and contributions to the field of energy balance and cancer.